N-hydroxyamidines (amidoximes) and N-hydroxyguanidines represent known prodrug principles for increasing the oral bioavailability of amidines [Clement, B. Methoden zur Behandlung und Prophylaxe der Pneumocystis carinii Pneumonie (PCP) und anderen Erkrankungen sowie Verbindungen und Formulierungen zum Gebrauch bei besagten Methoden, P 432-444.4, 1993] and guanidines.
Pharmaceutical preparations containing an active agent having one or more amidine or guanidine functions exhibit almost no pharmacological effect in oral application. The precondition for a therapeutical effect of an active agent after oral administration is represented by its resorption from the gastrointestinal tract. The most important mechanism of such an effect is passive diffusion. The degree of resorption by way of passive diffusion is dependent on the lipophilicity and thus also the acidity and basicity of the active agent.
Highly basic compounds such as amidines and guanidines are present in the stomach (pH 1) and small intestine (pH 6.4) in an almost completely protonated form. A resorption after oral administration, which requires the passing of lipid bilayers of the membranes of the gastrointestinal tract, therefore only occurs to a very low degree.
Another problem in the medication of many diseases is the necessity to cross the blood-brain barrier. The blood-brain barrier is an effective barrier with regard to the resorption of substances into the brain. It ensures the selective uptake and prevents the penetration of substances. Furthermore, the blood-brain barrier does no only act as a physical but also as an enzymatic barrier. Various processes are involved in the penetration of substances into the brain. As compared to other indications, only few drugs are marketed, which develop their effect in the central nervous system (CNS). The greater part thereof reaches the CNS by diffusion. Diseases like epilepsy, chronic pain or depressions are treated this way. Other serious functional disorders such as brain tumors or amyotrophic lateral sclerosis yet cannot be treated in this way today [PARDRIDGE, W. M. NeuroRx 2005, 2, 3-14]. For being able to cross the blood-brain barrier by way of passive diffusion, a substance is required to be lipophilic, have a lower molecular weight than 400-500 Da, and be present in an uncharged state. For resorbing specifically small molecules such as glucose or amino acids, various transporter systems such as nucleoside transporters, influx and efflux transporters for organic anions, glucose transporters, peptide transporters, and amino acid transporters are expressed on the blood-brain barrier [TAMAI, I.; TSUJI, A. J. Pharm Sci 2000, 89, 1371-1388 and DE BOER, A.; VAN DER SANDT, I. Annu Rev Pharmacol Toxicol 2003, 43, 629-656]. Larger molecules such as insulin or iron-containing transferrin are resorbed via the receptor-mediated transport. In this case, the insulin and transferrin receptors particularly play an important role [DE BOER, A.; VAN DER SANDT, I. Annu Rev Phamacol Toxicol 2003, 43, 629-656; PARDRIDGE, W. M. Mol Interv 2003, 3, 90-105]. Taking the amino acid L-dopa as an example, one has used a prodrug principle for the water-soluble catecholamine dopamine to be capable of passing the blood-brain barrier. The transport is performed by the amino acid transporter LAT1 (large neutral amino acid transporter). After the passage, the decarboxylation into dopamine takes place [PARDRIDGE, W. M. Mol Interv 2003, 3, 90-105].
Diamidines are used as antiparasitic agents against malaria, pneumocystis jiroveci (previously carinii) pneumonia, trypanosomiasis (African sleeping sickness), and leishmaniasis [WERBOVETZ, K. Curr Opin Investig Drugs 2006, 7, 147-157]. Particularly in developing countries, these diseases represent a serious problem involving high mortality rates.
Three diamidines to be applied parenterally are on the market. Pentamidine (Pentacarinat®) has been used in the early stage of the African sleeping sickness already for 60 years. Efficiency is no longer provided in the 2nd stage of the African sleeping sickness, the meningo-encephalitic stage, since the blood-brain barrier cannot be passed successfully. As a result, highly toxic arsenic compounds must be administered. There is a lack of medicinal substances which are efficient in the 2nd stage of the African sleeping sickness.
It is likely that all of the active agents, which have an amidine or a guanidine as a functional group, exhibit an insufficient resorption in the oral application, if they can only be resorbed by passive diffusion.
The N-hydroxylated derivatives such as amidoximes, and the N-hydroxyguanidines, due to the introduction of the oxygen atom, exhibit a lower basicity. Under physiological conditions, they are not present in a protonated form. Benzamidoxime represents a model compound for many medicinal substances containing an amidoxime function [Clement, B., Drug Met Rev 2002, 34, 565-579].
Pentamidine and diminazene represent diamidines and are not resorbed after oral application. They were therefore transferred into amidoxime prodrugs. (DE 10 2006 034 256.9).
The example pentamidine demonstrates that the transfer into the pentoxime ester also entails a reduction of the solubility. This probably is also the reason for the bioavailability of pentamidine not to reach one hundred percent after oral application of the pentoxime ester [Clement, B.; Bürenheide, A.; Rieckert, W.; Schwarz, J., ChemMedChem 2006, 1, 1260-7].
Furthermore, the reduced water solubility induces the disadvantage that an administration of the medicinal substance is no longer possible by injecting aqueous solutions. This is a problem, particularly when an oral administration is out of question.
It is therefore the task of the present invention to increase the water solubility and thus also the oral bioavailability of substances, which had been transferred into amidoxime prodrugs or N-hydroxyguanidine prodrugs, and/or thus to enable the passing of the blood-brain barrier.
The task is solved by methods according to embodiments of the invention, such as those methods having the features of the independent claim, and those methods having the additional features of the dependent claims, which indicate advantageous arrangements of the invention.